t's not uncommon for uterine cancer survivors to worry about recurrence. Whether you've had a recurrence or want to become more informed, join Dr. Susan C. Modesitt, Director of Gynecologic Oncology at UVA Cancer Center, to learn more information about uterine cancer recurrence as well as available treatment options.

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Cancer, Endometrial Cancer, and
Recurrence
Susan C. Modesitt, MD, FACOG, FACS
Professor and Director
Gynecologic Oncology Division
University of Virginia Health System
Talk Overview
• Cancer Definitions
• Cancer in the U.S.
• Cancer Causes
• Genetics of Cancer
• Hereditary syndromes in Uterine cancer
• Cancer treatment options
• Treatment of recurrent endometrial
cancer
Cancer Definitions
• An abnormal growth of cells that
proliferate in an uncontrolled manner
and invade other areas
• Can involve/start in any type of tissue
• Types/Classifications
– Carcinomas arise from skin or mucosal surfaces
– Sarcomas arise from muscle/connective tissues
– Leukemia arises in the blood forming tissues
– Lymphomas are from the immune system
Cancer in the U.S
• 23.3 million adults with cancer
• 9.4% of all adults have had cancer
• 600,000 deaths annually in the United
Stages
• Second leading cause of death (pre-
Covid)
Trends in US Cancer Mortality

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Cancer Causes
• Environmental (80-90% of cancer)
– Smoking and Tobacco
– Diet and Physical Activity (Obesity)
– Sun and Radiation Exposure
– Viruses and other infections (HPV)
– Carcinogens
• Hereditary (5-20% of cancer)
– Inherited mutations in genes that cause cells to
grow and metastasize
Preventable Causes of Cancer
• Obesity will soon overtake tobacco as the
leading cause of preventable cancer
Thirteen Obesity Associated
Cancers
CDC vital Signs, October 2017
Genetics
What now?
The Genome
• 3 billion base pairs
• 40,000 + genes
• Coding for our vital
proteins
• The more we know,
the more complicated
it gets
All Cancer is “Genetic”
• Cancer cells have genetic
alterations/mutations that
enable them to grow and
invade
• Not everyone with an altered
gene develops cancer
• Many factors involved in
acquisition of mutations and
cancer development
– Carcinogen exposures like x-
rays, sun damage, tobacco
– Life style factors like diet,
exercise, hormones, obesity,
inflammation,etc.
– Modifier genes
– Ability to repair DNA damage

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Oncogenes (examples KRAS, BRAF, CDK4)
• Cause increased cell (tumor/cancer) growth
• Normal tight regulation is lost with mutation, with subsequent
increase in growth
Tumor suppressor genes (examples: BRCA 1, Lynch)
• Work to restrain cell growth, fix errors
• With mutation, activity is lost, and uncontrolled cell growth
ensues
• Act as recessive genes, requiring loss of both copies of gene
pair to result in disease
• Inheritance of germline mutation predisposes to early-onset
cancers
• This is the most common type of genetic etiology of cancer
syndromes
Types of Cancer Genes Germline (inherited) Genetic Testing
Examples of genes on panel testing (not all listed!!!—
most panels up to 80 genes now)
APC CHEK 2 PTEN
ATM EPCAM RAD 50, 51 C/D
BARD1 MLH1 SMAD4
BMPR1A MSH2 STK-11
BRCA1 MSH6 TP53
BRCA2 MUTYH WTF***
BRIP1 NBN
CDH1 NF-1
CDK4 PALB 2
CDKN2A PMS2
Somatic versus Germline
mutations
• Somatic – mutation present in cancer tissue only
• Examples: p53 mutations found in malignant ovarian tumor or
papillary serous endometrial cancer or K-ras mutations in
endometrial cancers
• Germline – mutation is present in all cells and
was almost always transmitted from a parent with
the same mutation
• Example: BRCA 1 mutation from a mother or MSH 6 mutation
(Lynch mutation) from a father
Clues to Hereditary Cancer syndromes
• Early age at cancer diagnosis (<50)
• Related cancers in ≥2 family members on the
same side (maternal or paternal)
• Specific combination of cancers
– Breast and Ovarian
– Endometrial/colon/ovarian
– Breast/endometrial/thyroid
• Multiple rare cancers
• Multiple primary tumors in the same person
• 3-9% uterine cancer due
to inherited (germline)
mutation
– Lynch syndrome accounts
for majority
– PTEN
– POLD
– BRCA1  papillary serous
– TP53  Leiomyosarcoma
Ring KL et al. Mod Path 2016; 29(11): 1381-1389
Hereditary Uterine Cancer
Lynch Syndrome
• Mutation in mismatch repair genes
– MLH1, MSH2, MSH6, PMS2 and EPCAM
– Autosomal dominant (1 in 600)
• Hallmark cancers
– Colon
– Endometrial
– Ovarian
– Gastric
– Small bowel
– Renal pelvis
– Prostate

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Endometrial Cancer Patients
• High risk features merit germline genetic
testing
– Young age at diagnosis
– Family cancer history (esp. Lynch tumors)
• Universal tumor screening (somatic
testing) more prevalent after about 2012
• Testing can be done on prior tumor blocks
– For both genetics and immunotherapy decisions
Universal Tumor “Screening” for Lynch
Syndrome
• Endometrial cancer/Colon cancer
• Screen the tumor itself for signs of defects
in the mismatch repair protein function
– Immunohistochemistry for expression of the
proteins (MSH 2,MSH 6, MLH1 and PMS2)
– Microsatellite instability DNA testing
– If these screens are positive OR a concerning
family history, then do definitive germline
testing
MMR Expression on IHC
Intact expression
MMR intact
Loss of expression
MMR deficient
Respond best to
immunotherapy
Cancer Treatment Options
• Surgery
• Radiation
• Chemotherapy*
• Some combination of the above
modalities
* Includes hormones, targeted therapy,
immunotherapy etc
Surgery:
A chance to cut is a chance to cure

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Radiation Chemotherapy
• Standard cytotoxic agents
– essentially poisons that kill
cells that divide quickly
• Targeted agents
– Block specific growth
pathways
• Immunotherapy
– Stimulate person’s immune
system to kill the cancer
Endometrial Cancer
Endometrial Cancer Risks
Factor Relative Risk
Hereditary Non-Polyposis Colon 6-10
Cancer (HNPCC)
Obesity 50 lbs over IBW 10
Chronic unopposed estrogen 9.5
Tamoxifen therapy 7.5
Obesity 30 lbs over IBW 3
Diabetes 2.8
Nulliparity 2
Hypertension 1.5
Endometrial Cancer Staging
Stage I Confined to the Uterus
IA Tumor limited to the endometrium or up to ½ of the
myometrium
IB Tumor invades greater than ½ of the myometrium
Stage II Involves the cervical stroma
Stage III Pelvic extension
IIIA Tumor involves the uterine serosa or the adnexa
IIIB Vaginal involvement
IIIC Pelvic or para-aortic lymph nodes are positive
Stage IV Distant disease
IVA Tumor invades bowel or bladder mucosa
IVB Distant disease including intraabdominal disease or
positive inguinal lymph nodes
Endometrial Cancer Treatment
• Surgical resection and staging is mainstay
• Stage I cancers predominantly treated with
surgery
– Postoperative radiation considered for risk factors
– Adjuvant chemotherapy for aggressive subtypes like
papillary serous or clear cell
• Advanced cancers are treated with
combination of surgery followed by radiation
and/or chemotherapy
– Potential role also for immunotherapy

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Uterine Sarcomas
• Account for 4% of uterine tumors *
– Leiomyosarcoma
– Endometrial stromal sarcoma
• More aggressive tumors with early spread
• Treatment includes surgery/staging with
possible adjuvant radiation
• Account for 26% of deaths from uterine cancer
*Included carcinosarcoma until recently
Matei Review
Stage 5 year survival
I 78-90%
II 74%
III 36-57%
IV 20%
ACS
J Gynecol Oncol. 2014 Apr; 25(2): 136–147.
Types of endometrial cancer
• Type I – Endometrioid cell type
– Often occurs in the presence of hyperplasia
– Related to hormones
– Excellent overall prognosis
• Type II – Serous, clear cell,
carcinosarcoma, grade III endometrioid
– Often occurs in the presence of a thin
endometrium
– Not related to hormones
– More likely to spread
Types of endometrial cancer-
beyond basic histology
• Endometrial cancers analyzed with the TCGA
(The Cancer Genome Atlas) have identified 4
molecular subtypes
1. POLE (polymerase epsilon) ultra-mutated
• Associated with the BEST clinical prognosis
2. Microsatellite High (MMR deficient)
• Associated with intermediate prognosis
3. Copy number high*
• Associated with the WORST clinical prognosis
4. Copy number low*
• Associated with intermediate prognosis
* Copy number can be estimated by p53 expression
Recurrent Endometrial Cancer

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Treatment Options for
Recurrent Endometrial Cancer
• Surgery (Local treatment)
– Isolated site of recurrence
• Radiation (Local treatment)
– Small recurrences that are unresectable (vaginal/nodal)
• Chemotherapy (Systemic treatments)
– Standard cytotoxic chemotherapy
– Hormonal therapy
– Immunotherapy
– Targeted therapies
– Clinical trials
NCCN Guidelines-2022
Tumor testing considerations in
recurrent endometrial cancer
• MMR protein testing if not done
previously
• Hormone receptors
– Estrogen and progesterone
• Consider tumor mutational burden
(TMB)
• Consider NTRK gene fusion
• Consider Her-2-neu (serous cancers)
Case 1
• 60 year old with a history of a vaginal
hysterectomy 4 years prior with an
unstaged but presumed Stage IA, grade
1 cancer (3/13 mm invasion)—no lymph
nodes and never saw an oncologist
• CT performed a year after surgery was
negative
• Had pain and CT scan 4 years after
surgery showed a 6 cm solid right
adnexal mass, Ca-125 of 53
CT scan Case 1
• Underwent exploratory laparotomy and extensive
lysis of adhesions (small and large bowel and mass),
lasting 30 minutes.
• Optimal tumor removal (debulking) to no visible
residual tumor and tumor appeared to be within the
right ovary (or remnant). Grade 1 endometrioid
cancer, MMR intact
• Whole pelvic radiation
• Discussion of hormone therapy but she opted for
surveillance only
• Alive without disease now 5 years later

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Standard Chemotherapy options
for Recurrent Endometrial
Cancer
People are in internet/media
cancer information overload
What are patients and
physicians to do?
Standard Chemotherapy
• Paclitaxel (Taxol) and Carboplatin is
standard first line therapy
• Alternatively
– Any Taxane/Platinum
• Taxane/platinum with bevacizumab (Avastin)
• Taxane/platinum with trastuzumab (serous)
– Doxorubicin (liposomal or otherwise)
– Ifosfamide/paclitaxel (carcinosarcoma)
– Topotecan
Slide stolen with permission from
Dr. Marcela Del Carmen
ORR=overall response rate

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Statistics according to Mark
Twain
“There are lies, damn lies, and statistics”
Targeted therapy options
for Recurrent Endometrial
Cancer
Targeted Therapies
• Bevacizumab (Avastin)
– Antibody against VEGF which allows cancer
cells to recruit their own blood supply
• Trastuzumab (Herceptin)
– Antibody against Her-2-Neu in serous cancers
that carry this marker
• MTOR inhibitors
– Temsirolimus
– Everolimus
• Larotrectinib (NTRK gene fusion)
MTOR inhibitors
Everolimus
Temsirolimus
Often used in conjunction with
estrogen blockade and most often
endometrioid tumor types
PI3K/AKT/mTOR Pathway Temsirolimus-Phase II NCIC
trial (Oza et al)
• Women with noncurable recurrent
endometrial cancer
• Temsirolimus 25 mg IV weekly
• Results in 27 patients
– 7% partial response, 44% stable disease
– Median progression free survival was 3.5
months

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Everolimus and letrozole in recurrent
endometrial cancer (Slomovitz, 2015)
● Overall response rate
was 31%
● 40% had prolonged
stable disease
● Median OS 14 mos
● Median PFS 3 mos
GOG-3007
● Non-comparative randomized phase II
trial to determine response and
progression free survival of patients
treated with everolimus and letrozole
therapy (EL) and medroxyprogesterone
acetate and tamoxifen therapy (PT)
Everolimus/letrozole Side
effects
• Fatigue is most common but often
improves
• Stomatitis-66% (mouth sores), should
start preventative mouth washes as soon
as therapy starts
• Nausea
• Metabolic issues (increased blood sugars
and cholesterol that may require
treatment)
Immunotherapy options
for Recurrent Endometrial
Cancer
Goal is to stimulate the immune system to
recognize the cancer as foreign and kill it
Immunotherapy options
for Recurrent Endometrial
Cancer
Pembrolizumab*
Pembrolizumab/lenvatinib
Nivolomab*
Dostarlimab*
Avelumab*
* Require dMMR or high mutational burden for approval
Immunotherapy: PD pathways

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U.S. Food and Drug Administration.FDA approvalto pembrolizumabfor first tissue/site agnostic
indication.Available https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm560040.htm.
Pembrolizumab
Currently approved for:
1. MMR deficient tumors (MSI high)
2. High tumor mutational burden
Pembrolizumab Side effects
• Fatigue
• Immune related side effects
– Colitis
– Pneumonitis
– Pancreatitis
– Hypothyroid
– Inflammatory arthritis
– Can occur up to a year after completion of
treatment
Lenvatinib (20 mg PO daily)
Pembrolizumab (200 mg IV q 3 weeks)
38% response rate
Of responders:
87% responded for > 6 months
Lenvatinib/pembrolizumab
Side effects
• Hypertension is most common (32%) due
to the lenvatinib
• Fatigue
• Diarrhea
• Hypothyroidism (47%) that may require
replacement
• Immune related side effects (colitis,
pneumonitis, pancreatitis etc.)

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Hormone therapy options
for Recurrent Endometrial
Cancer
Types of Hormones
• Progestins
– Medroxyprogesterone (Provera)
– Megestrol (Megace)
• Estrogen blockers
– Aromatase inhibitors (letrozole, anastrozole)
– Fulvestrant
• Selective estrogen receptor modifiers
(SERM)
– Tamoxifen
– Raloxifene (Evista)
Phase II GOG trial
• Women with noncurable recurrent
endometrial cancer
• Megace 80 mg orally twice daily for 3
weeks alternating with tamoxifen 20 mg
orally twice daily for 3 weeks
• Results
– 21% complete response, 5.4% partial response
– Median progression free survival was 2.7
months, overall survival was 14 months
– 53% of responders maintained over 20 months
Cancer Clinical Trials:
The Good
• Huge advances in patient care
– Cures for multiple malignancies
• Gestational trophoblastic tumors
• Germ cell ovarian tumors
• Pediatric malignancies
– Improved survival
• 1999 NCI alert for the addition of platinum based
chemotherapy to radiation for cervical cancer
• Elucidation of new targets/pathways continues
– Thousands of anticancer medicines/vaccines in
development
Cancer Clinical Trials:
The Bad
• Limited success rates for most new
cancer therapies undergoing trials
– Estimated at 5% of agents
• Majority fail in late stage development
– Most due to lack of efficacy
– Sadly, tremendous resources already have been
deployed before the failure
Cancer Clinical Trials:
The Ugly
• Costs are astronomical
– Estimates vary but the cost of putting a patient
on a treatment trial is $7-8,000
– NCI funded groups receive $2,000 per patient
• Less than 5% of eligible patients are put
on trial
– Women vastly under-represented
– Minorities also very under-represented

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Phases of Clinical Trials
In Phase I trials, researchers test an experimental drug or
treatment in a small group of people (20-80) for the first time to
evaluate its safety, determine a safe dosage range, and identify
side effects.
In Phase II trials, the experimental study drug or treatment is
given to a larger group of people (100-300) to see if it is effective
and to further evaluate its safety.
In Phase III trials, the experimental study drug or treatment is
given to large groups of people (1,000-3,000) to confirm its
effectiveness, monitor side effects, compare it to commonly used
treatments, and collect information that will allow the
experimental drug or treatment to be used safely.
In Phase IV trials, post marketing studies delineate additional
information including the drug's risks, benefits, and optimal use.
Lifted verbatim from
http://www.clinicaltrials.gov/
Conclusions
• Things are changing rapidly in cancer
• We are getting more options to offer
patients especially in endometrial cancer
• Always need to personalize treatment
decisions
• Clinical trials crucial to move progress
Questions? Pembrolizumab for PD-L1+ Endometrial
cancers
Other trials
Q3 week Taxol 175mg/m2 q3w ORR 25% among Taxol-naïve
patients
GOG 129C
(Gyn Onc, 2003)
Lincoln, et al.
Weekly Taxol 80mg/m2 q 1w ORR 20.9% among plat-
resistant and Taxol-q3w-
resistant.
GOG
Gyn Onc, 2006
Markman, et al.
Doxorubicin 60mg/m2 q 3w Extrapolated (1st-linedata)
ORR ranging 19-37%
Bevicizumab (SA) Bev 15mg/kg q3w IV 13.5% ORR, med DOR 6m
PFS 4.2m, OS 10.5m
GOG 229-E (JCO, 2011)
Phase II trial
Aghajanian, et al
Doxil (SA) Doxil 50mg/m2 IV
q4w
ORR 9.5%
Med OS 8.2m
GOG 129H (JCO, 2002)
Phase II trial
Muggia, et al.
Temsirolimus (SA) 25mg IV weekly -in prior chemo-rx grp…
4% PR, 48% SD w/ med
dDOR 3.8m
Med PFS 3.25m
NCIC CTG
JCO, 2011
Ivy, et al
Temsirolimus +
Bevicizumab
Bev 10mg/kg q2 w
Temsirolimus 25mg
weekly
ORR 25%
Med PFS 5.6m
Median OS 16.9m
GOG 229-G
Gyn Onc, 2013
Alvarez, et al
Everolimus +
Letrozole
Everolimus 10mg +
Let 2.5mg po daily
CBR (CR+PR+SD)=40%
ORR 32%
(JCO, 2015)
Phase II trial
Slomovitz, et al
Hormone trials summary
Megace/Tamoxifen
(Rec or advanced)
Tamoxifen 20mg BID x3
weeks then Megace
80mg BID x3 weeks
alternating
No prior cytotoxic or
hormonal treatment
ORR 27% (38% in gd1,
24% in gd2, 22% in gd3)
PFS 2.7m, OS 14m
GOG 153
Gyn Onc, 2004
Fiorica, et al.
Letrozole
(Rec or advanced)
Letrozole 2.5mg daily
continuously
ORR 9.4%, 11/28 SD w/
med duration 6.7m;
PFS 3.9m, OS 8.8
Ma, et al
Int J Gyn Cancer, 2004
Anastrazole
(Rec or advanced)
Anastrazole 1mg/day
orally for at least 28d
2 PR (9%), 2 SD (9%).
PFS 1m, OS 6m
Rose, et al. GOG 168
Gyn Onc 2000
Megace alone
(red or advanced)
Megace 800 mg/d ORR 24% (11% CR, 13%
PR); 22% SD
PFS 2.5m, OS 7.6m
Lentz, et al
Gyn Onc, 1996
GOG 121
Goserelin acetate IM 3.6mg monthly ORR 11%
PFS 1.9m, OS 7.3m
Asbury, et al.
Am. JCO, 2002
Tamoxifen Tamoxifen 20mg BID ORR 10%
PFS 1.9m, OS 8.8
GOG 81F
Thigpen, et al